Each year, nearly 30 million general anesthetics are administered in the U.S. alone. At the concentrations required to produce anesthesia, all general anesthetics produce potentially serious and sometimes deadly side effects. Of particular concern is depression of cardiovascular and respiratory function, which can be life threatening, particularly in elderly, sick, and traumatized patients. These deleterious side effects are caused by nearly all general anesthetics and explain why anesthetics have among the lowest therapeutic indices (LD50/ED50) of any class of therapeutic drugs. Therefore, there is great value in developing safer anesthetic agents with fewer side effects.
Etomidate (ethyl 3-(1-phenylethyl)imidazole-4-carboxylate) is a rapidly acting imidazole-based I.V. sedative-hypnotic that can be used to induce and maintain general anesthesia or conscious sedation. It exists as two enantiomers; however, the (R)-enantiomer is ˜10-fold more potent an anesthetic than the (S)-enantiomer. The (R)-enantiomer is the one that is used clinically (see Structure 1, below). (R)-etomidate induces loss of righting reflexes in tadpoles (Husain, S. S., et al., J Med Chem, 46:1257-1265 (2003)) and loss of responsiveness in humans (Arden, J. R., et al., Anesthesiology, 65:19-27 (1986)) at a free-aqueous concentration of ˜2 μM.
